Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction.
Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction.
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DOI：
10.3389/fcell.2021.792051
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发表时间：
2021
影响因子：
5.5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Zhang S;Zhao S;Han X;Zhang Y;Jin X;Yuan Y;Zhao X;Luo Y;Zhou Y;Gao Y;Yu H;Sun D;Xu W;Yan S;Gong Y;Li Y
越来越多的证据表明，长链非编码RNA（lncRNA）在各种心血管疾病中起着重要的分子调节作用。在这里，我们的目的是确定和功能特性的lncRNA作为潜在的介质在胸主动脉夹层（CHD）的发展。我们发现了一种新的lncRNA，lnc-C2 orf 63 -4-1，低表达在血管紧张素II（Ang II）激发的血管平滑肌细胞（VSMCs），这与临床主动脉扩张患者的主动脉样品。此外，lnc-C2 orf 63 -4-1的过表达显著减弱了Ang II诱导的VSMCs凋亡、表型转换和细胞外基质降解。定制的转录因子阵列鉴定出信号转导子和转录激活子3（STAT 3）作为主要的下游效应子发挥作用。双荧光素酶报告分析和RNA反义纯化（RAP）实验表明，lnc-C2 orf 63 -4-1通过降低STAT 3 mRNA的稳定性直接降低STAT 3的表达。重要的是，上调STAT 3有效地逆转了lnc-C2 orf 63 -4-1对Ang II介导的血管重塑的保护作用。因此，lnc-C2 orf 63 -4-1负性调节STAT 3的表达，并防止主动脉夹层的发展。我们的研究表明，lnc-C2 orf 63 -4-1在血管稳态中起着关键作用，其功能障碍加剧了Ang II诱导的病理性血管重构。
Emerging evidence indicates that long non-coding RNAs (lncRNAs) serve as a critical molecular regulator in various cardiovascular diseases. Here, we aimed to identify and functionally characterize lncRNAs as potential mediators in the development of thoracic aortic dissection (TAD). We identified that a novel lncRNA, lnc-C2orf63-4-1, was lowly expressed in aortic samples of TAD patients and angiotensin II (Ang II)-challenged vascular smooth muscle cells (VSMCs), which was correlated with clinically aortic expansion. Besides, overexpression of lnc-C2orf63-4-1 significantly attenuated Ang II-induced apoptosis, phenotypic switching of VSMCs and degradation of extracellular matrix both in vitro and in vivo. A customized transcription factor array identified that signal transducer and activator of transcription 3 (STAT3) functioned as the main downstream effector. Mechanistically, dual-luciferase report analysis and RNA antisense purification (RAP) assay indicated that lnc-C2orf63-4-1 directly decreased the expression of STAT3, which was depend on the reduced stabilization of STAT3 mRNA. Importantly, up-regulation of STAT3 efficiently reversed the protective role of lnc-C2orf63-4-1 against Ang II-mediated vascular remodeling. Therefore, lnc-C2orf63-4-1 negatively regulated the expression of STAT3 and prevented the development of aortic dissection. Our study revealed that lnc-C2orf63-4-1 played a critical role in vascular homeostasis, and its dysfunction exacerbated Ang II-induced pathological vascular remodeling.
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